Topical formulation for delivery of interleukin-11

ABSTRACT

Provided by the present invention are topical formulations of Interleukin-11 and methods for treating a variety of disorders, including inflammatory bowel diseases (e.g., Crohn&#39;s disease, ulcerative colitis, indeterminate colitis, and infectious colitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis, and proctitis), necrotizing enterocolitis, inflammatory skin disorders (e.g., psoriasis, atopic dermatitis, and contact hypersensitivity), aphthous ulcers, pharyngitis, esophagitis, peptic ulcers, gingivitis, periodontitis, and ocular diseases (e.g., conjunctivitis, retinitis, and uveitis).

RELATED APPLICATION(S)

This is a Continuation of U.S. application Ser. No. 09/179,026, filedOct. 26, 1998, which is a continuation-in-part of U.S. application Ser.No. 08/892,407, filed Jul. 15, 1997, which is a divisional of U.S.application Ser. No. 08/495,724, filed Jun. 27, 1995, now Pat. No.5,679,339, issued Oct. 21, 1997, the entire teachings of which areincorporated herein by reference.

FIELD OF INVENTION

The present invention relates generally to novel compositions andmethods for topical delivery of interleukin-11 (IL-11). In preferredembodiments, patients are treated employing topical delivery ofrecombinant human IL-11 for inflammatory bowel diseases (e.g., Crohn'sdisease, ulcerative colitis, indeterminate colitis, and infectiouscolitis), mucositis (e.g., oral mucositis, gastrointestinal mucositis,nasal mucositis, and proctitis), necrotizing enterocolitis, inflammatoryskin disorders (e.g., psoriasis, atopic dermatitis, and contacthypersensitivity), aphthous ulcers, pharyngitis, esophagitis, pepticulcers, gingivitis, periodontitis, and ocular diseases (e.g.,conjunctivitis, retinitis, and uveitis).

BACKGROUND OF THE INVENTION

Inflammatory responses include a broad range of host reaction to avariety of insults, such as injury, infection, or rejection. It is theoverproduction of mediators that is believed to be associated with abroad range of disorders, including AIDS, arthritis (rheumatoidarthritis, osteoarthritis, spondyloarthropathies), antibiotic-induceddiarrheal diseases, multiple sclerosis, osteoporosis, gingivitis, pepticulcer disease, esophagitis, diabetes, retinitis, uveitis, reperfusioninjury after myocardial infarction, cerebral vascular accident, aphthousulcers (oral), atherosclerosis, tumor metastases, asthma, preeclampsia,pancreatitis, psoriasis, infertility and allergic disorders such asrhinitis, conjunctivitis, and urticaria.

Some of these disorders and their symptoms are briefly summarized below.According to the methods of the present invention, IL-11 is administeredtopically to modulate the host's over reaction at the site of insult,thereby treating the following disorders.

Inflammatory Bowel Disease: Inflammatory bowel disease is the termgenerally applied to four diseases of the bowel, namely Crohn's disease,ulcerative colitis, indeterminate colitis, and infectious colitis.

Ulcerative Colitis: Ulcerative colitis is a chronic inflammatory diseaseof unknown etiology afflicting the large intestine. The course of thedisease may be continuous or relapsing, mild or severe. The earliestlesion is an inflammatory infiltration with abscess formation at thebase of the crypts of Lieberkühn. Coalescence of these distended andruptured crypts tends to separate the overlying mucosa from its bloodsupply, leading to ulceration. Signs and symptoms of the disease includecramping, lower abdominal pain, rectal bleeding, and frequent, loosedischarges consisting mainly of blood, pus, and mucus with scanty fecalparticles. A total colectomy may be required for acute severe orchronic, unremitting ulcerative colitis.

Crohn's Disease: Crohn's disease (also known as regional enteritis orulcerative ileitis) is also a chronic inflammatory disease of unknownetiology but, unlike ulcerative colitis, it can affect any part of thebowel. The most prominent feature of the disease is the granular,reddish-purple edematous thickening of the bowel wall. With thedevelopment of inflammation, these granulomas often lose theircircumscribed borders and integrate with the surrounding tissue.Diarrhea and obstruction of the bowel are the predominant clinicalfeatures. As with ulcerative colitis, the course of the disease may becontinuous or relapsing, mild or severe but, unlike ulcerative colitis,it is not curable by resection of the involved segment of bowel. Mostpatients with Crohn's disease require surgery at some point, butsubsequent relapse is common and continuous medical treatment is usual.

Mucositis: Mucositis involves ulcerative breakdown of mucosal epithelialtissue, and is literally defined as inflammation of the mucous membrane.The pathophysiology of mucositis in response to toxic insults to themucosa by chemotherapy or by ionizing radiation is complex and involvesa cascade of interactions among cells, cytokines and the oralmicroflora. The underlying premise for susceptibility of the mucosa ofthe oropharynx and gastrointestinal tract to chemotherapy or radiationdamage is related to rapid epithelial stem cell turnover. Mucositis maybe characterized by the following phases:

1. Early inflammatory phase characterized by release of inflammatorycytokines in response to local tissue damage caused by cytotoxicagent(s);

2. Epithelial phase characterized by death of basal cells, which hindersre-population of the epithelium. This inability to regenerate leads toatrophy followed by ulceration. The ulceration represents loss of animportant anatomic barrier at a site of local microflora;

3. Infection phase characterized by local invasion of microflora thatresults in an inflammatory response to the local infection. Theinflammation results in additional local tissue damage and possiblyerosive ulceration; and

4. Healing phase characterized by resolution of the infection andregeneration of epithelium.

Oral mucositis produces the following clinical symptoms and signsresulting from cellular damage: 1) sensation of dryness; 2) asymptomaticredness and erythema; 3) solitary white elevated desquamative patcheswhich are painful upon pressure contact; and 4) large, painful,contiguous pseudomembranous lesions associated with dysphagia anddecreased oral intake. These spontaneously painful lesionshistopathologically show loss of epithelial cells to the basementmembrane, which exposes the connective tissue stroma with its associatedinnervation.

As with oral mucosa, gastrointestinal mucosal damage results fromdisturbance of cellular mitosis that leads to reduction in the turnoverrate of the basal cells of the intestinal crypts. The symptoms and signsof gastrointestinal mucositis include tenesmus (painful ineffectualstraining at stool), pain, bleeding, diarrhea, telangectasia(neovascularization), and progression to ulceration. Early signs ofdiarrhea include increased stool frequency, loose or watery stool, foodaversion, increased bowel sounds, abdominal pain, and some loss of skinturgor indicative of dehydration. When the diarrhea is severe it may beassociated with mucosal ulceration, bleeding, intestinal perforation andproctitis. Stool exam may reveal occult blood and fecal leukocytes.

Necrotizing Enterocolitis: Necrotizing enterocolits is an inflammatorydisease of unknown etiology that afflicts between 1-5% of all infantsadmitted to neonatal intensive care units, most of whom are prematureinfants. Signs and symptoms include abdominal distention,gastrointestinal hemorrhage, and feeding intolerance. The disease mostoften involves the ileum and colon, and is characterized by loss ofepithelium and submucosal edema, ulcerations, and, in severe cases,transmural necrosis.

Psoriasis: Psoriasis is a chronic inflammatory skin disorder involvinghyperproliferation of the epidermis and inflammation of both theepidermis and the dermis. Macrophage, T-cells and neutrophilinfiltration of the dermis and epidermis is seen, and proinflammatorymediators are released from these activated cells.

Aphthous Ulcers (oral): Although the cause of aphthous ulcers remainunknown, many physicians believe they are caused by autoimmunephenomena, which cause the destruction of discrete areas of the oralmucosa which leads to oral ulceration. Among the cytokines present inthese active areas of ulceration, TNF-α appears to play a predominantrole.

Gingivitis: Adult periodontitis is strongly associated with infection byPorphyromonas gingivalis. Proteolytic enzymes, which are produced inlarge quantity by this bacteria, are considered as important pathogenicagents. The increased production and flow of gingival crevicular fluid(GCF) is an important change in gingival tissues during periodontalinfection, correlating with clinical indices of gingival inflammation.Indeed, salivary protein and albumin concentrations of individuals withperiodontitis, which are an indication of plasma leakage due to vascularpermeability enhancement (VPE), are significantly increased compared tohealthy subjects. The production of GCF appears dependent on VPE inducedat periodontitis sites, presumably involving proteinase(s) of P.gingivalis in their generation.

Esophagitis: The most common cause of esophagitis is the chronic refluxof hydrochloric acid from the stomach due to inefficiency of the cardiacsphincter of the stomach. The chronic presence of acid in the loweresophagus leads to damage of the esophageal mucosa. In the most severeform, a syndrome called Barrett's esophagus can develop which oftenleads to esophageal cancer. Other causes of esophagitis includeparenteral chemotherapy and ionizing radiation, associated withradiation therapy for cancer in the thoracic cavity.

Retinitis: Inflammation of the light sensitive retina, retinitis, canoccur due to a variety of viral, bacterial or autoimmune etiologies. Theend result is destruction of the retina and loss of sight.

Uveitis: Inflammation of the anterior portion of the eye its associatedstructures, the iris and cornea occurs with a relatively high frequencyin patients with autoimmune disorders.

Peptic Ulcer Disease: Inhibition of gastric acid secretion withH₂-receptor antagonists and, more recently, blockers of H⁻,K⁻-ATPase(also known as the proton pump) has been the mainstay of therapy forpeptic ulcer disease. The pathophysiology of peptic ulcers remainsobscure. An appreciation of the complexity of the physiology of thegastric mucosa has led to a hypothesis that peptic ulcers are the resultof an imbalance in the relative importance of aggressive (acid, pepsin)and protective (mucus, bicarbonate, blood flow, prostaglandins, etc.)factors. Infection of the mucosa of the human gastric antrum with thebacterium Helicobacter pylori has been widely accepted as the cause ofchronic, active, type B gastritis. Further, this form of gastritis hasbeen linked directly to peptic ulcer disease by studies showing thateradication of H. pylori reverses this gastritis and prevents duodenalulcer relapse. Because cytokines are the principal mediators by whichimmune/inflammatory cells communicate with each other and with othercells, it is likely that these small peptides are involved in thepathogenesis of chronic active type B gastritis and the resulting pepticulcer disease.

Some cytokines (IL-1, epidermal growth factor, transforming growthfactor-α, acidic and basic fibroblast growth factors) tip the balancetowards peptic ulcer healing; others (tumor necrosis factor-α) appear tohave no effect; still others (IL-4) may even cause gastrointestinaldamage.

The infiltration and activation of multiple types of inflammatory cellsresult in a series of degenerative changes in the vasculature of theaffected area, as well as inciting damage of the surrounding parenchymaltissue.

SUMMARY OF THE INVENTION

Provided by the present invention are novel compositions for the topicaladministration of IL-11 in order to treat a number of disorders wheresuch administration is preferable to systemic administration. Among thereasons that local administration may be preferred are the ease ofadministering a topical formulation compared to administration ofsubcutaneous injectable formulations. In certain classes of patients,the toxicity profile of chemotherapeutic agents may be such thatconcurrent parenteral administration of IL-11 is relatively unsuited.Other patients may have medical conditions for which the adverse eventprofile of parenteral IL-11 is relatively unsuited.

According to the present invention, IL-11, analogs, and derivativesthereof, are administered to patients, either prophylactically or at theonset of symptoms associated with the aforementioned disorders, throughone of several forms of local administration described below. IL-11 canbe administered in suitable pharmaceutically acceptable carriers eitheralone or in combination with other conventional agents useful inalleviating the symptoms associated with the aforementioned disorders.

In one embodiment, the present invention comprises preparations of IL-11which are suitable for oral delivery to the mouth. Suitable oralpreparations may be prepared with aqueous-based solutions such as sodiumbicarbonate (e.g., Brioschi®), or in gels and suspensions for topicaladministration in the mouth. Oral preparations may also take the form ofpatches for delivery of IL-11 to the mouth via sustained release.Additional oral preparations may comprise IL-11 in the form of a lozengeor an uncoated tablet which is retained in the mouth. The oralpreparations are particularly well-suited for disorders and inflammatoryresponses involving the mucosa of the head, neck and/or mouth. Suchconditions include oral mucositis, pharyngitis, esophagitis, gingivitis,periodontitis, and aphthous ulcers (oral). Such conditions may result,for example, from chemotherapy or radiotherapy for head and neck cancer,cervical esophageal cancer or lung cancer.

In other embodiments, the present invention comprises preparations ofIL-11 which are suitable for topical delivery for mucosa and/or dermis.Such topical preparations may be prepared in the form of aqueous-basedsolutions, gels, ointments or creams for topical administration, as gelsand suspensions for cervical administration, as pills, tablets, capsulesor suppositories for immediate or sustained release to thegastrointestinal tract, or in the form of solution for enema. Suchtopical preparations are especially suited for treatment of disordersrelating to local regions, such as psoriasis, as well as inflammatorybowel disease, esophagitis, and gastrointestinal mucositis. Some ofthese conditions may result, for example, from chemotherapy and/orradiotherapy for colorectal cancer, prostate cancer, cervical esophagealcancer or lung cancer.

Suitable doses of IL-11 are generally in the range of between about 1and about 250 μ/kg body weight, and may be administered from once a weekup to about six times daily. Treatment may continue for a period ofbetween one day and six months, or for as long as is deemed necessaryand safe in the treatment of the aforementioned disorders, as is readilyascertained by standard tests by the attending physician, depending uponthe nature of the disorder being treated.

DETAILED DESCRIPTION OF THE INVENTION

Provided by the present invention are methods and compositions fortopical administration of IL-11, for the treatment of various disorders,such as inflammatory bowel diseases (e.g., Crohn's disease, ulcerativecolitis, indeterminate colitis, and infectious colitis), mucositis(e.g., oral mucositis, gastrointestinal mucositis, nasal mucositis, andproctitis), necrotizing enterocolitis, aphthous ulcers, psoriasis,pharyngitis, esophagitis, peptic ulcers, gingivitis, periodontitis, andocular diseases (e.g., conjunctivitis, retinitis, and uveitis).

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice of the present invention, the preferred methods andmaterials are described. For purposes of the present invention, thefollowing terms are defined below.

As used herein, the term “topical” refers to application at the site ofinflammation (i.e., non-systemic administration), and includes, forexample, oral, intranasal, intrabronchial, topical, and rectal routes ofadministration. The term “topical formulation” refers to apharmaceutical formulation which is suitable for topical administrationof the active ingredient.

As used herein, the term “pharmaceutically acceptable” refers to acarrier medium which does not interfere with the effectiveness of thebiological activity of the active ingredient(s) and which is not toxicto the host to which it is administered.

As used herein, the terms “therapeutically effective amount” and“therapeutically effective dose” as applied to the active ingredientrefers to the amount of the component in the composition or administeredto the host that results in an increase in the therapeutic index of thehost. The “therapeutic index” can be defined for purposes herein interms of efficacy, i.e., extent of reduction or inhibition ofinflammation. Suitable doses of the active ingredient can be determinedusing well-known methods, a variety of which are known and readilyavailable in the pharmaceutical sciences, including, for example,measurement of markers associated with the disorder (e.g., TNF-α, IL-1β,IL-6, and/or IL-12 p40 mRNA), the biological effects of TNF-α, anddecreased symptomatology.

Interleukin 11 (IL-11) is a pleiotropic cytokine that stimulatesprimitive lymphohematopoietic progenitor cells and synergizes with otherhematopoietic growth factors to stimulate the proliferation andmaturation of megakaryocytes. IL-11 is described in detail inInternational Application PCT/US90/06803, published May 30, 1991, aswell as in U.S. Pat. No. 5,215,895; issued Jun. 1, 1993. A cloned humanIL-11 was previously deposited with the ATCC, 12301 Parklawn Drive,Rockville, Md., on Mar. 30, 1990 under ATCC No. 68284. Moreover, asdescribed in U.S. Pat. No. 5,270,181, issued Dec. 14, 1993, and U.S.Pat. No. 5,292,646, issued Mar. 8, 1994, IL-11 may also be producedrecombinantly as a fusion protein with another protein. IL-11 can beproduced in a variety of host cells by resort to now conventionalgenetic engineering techniques. In addition, IL-11 can be obtained fromvarious cell lines, for example, the human lung fibroblast cell line,MRC-5 (ATCC Accession No. CCL 171), and Paul et al., the humantrophoblastic cell line, TPA30-1 (ATCC Accession No. CRL 1583). A cDNAencoding human IL-11, as well as the deduced amino acid sequence (aminoacids 1 to 199), is described in Proc. Natl. Acad. Sci. USA 87:7512(1990). U.S. Pat. No. 5,292,646, supra, describes a des-Pro form ofIL-11 in which the N-terminal proline of the mature form of IL-11 (aminoacids 22-199) has been removed (amino acids 23-199). As is appreciatedby one skilled in the art, any form of IL-11 which retains IL-11activity, such as variants through the substitution or deletion of aminoacids, analogs and derivatives of IL-11, is useful according to thepresent invention. The disclosure of each of the above publications ishereby incorporated by reference for the contents thereof.

In addition to recombinant techniques, IL-11 may also be produced byknown conventional chemical synthesis. Methods for constructing thepolypeptides useful in the present invention by synthetic means areknown to those of skill in the art. The synthetically constructedcytokine polypeptide sequences, by virtue of sharing primary, secondary,or tertiary structural and conformational characteristics with thenatural cytokine polypeptides are anticipated to possess biologicalactivities in common therewith. Such synthetically constructed cytokinepolypeptide sequences or fragments thereof, which duplicate or partiallyduplicate the functionality thereof may also be used in the method ofthis invention. Thus, they may be employed as biologically active orimmunological substitutes for the natural, purified cytokines useful inthe present invention.

Modifications in the protein, peptide or DNA sequences of thesecytokines or active fragments thereof may also produce proteins whichmay be employed in the methods of this invention. Such modifiedcytokines can be made by one skilled in the art using known techniques.Modifications of interest in the cytokine sequences, e.g., the IL-11sequence, may include the replacement, insertion or deletion of one ormore selected amino acid residues in the coding sequences. Mutagenictechniques for such replacement, insertion or deletion are well known toone skilled in the art. (See, e.g., U.S. Pat. No. 4,518,584.)

Other specific mutations of the sequences of the cytokine polypeptideswhich may be useful therapeutically as described herein may involve,e.g., the insertion of one or more glycosylation sites. Anasparagine-linked glycosylation recognition site can be inserted intothe sequence by the deletion, substitution or addition of amino acidsinto the peptide sequence or nucleotides into the DNA sequence. Suchchanges may be made at any site of the molecule that is modified byaddition of O-linked carbohydrate. Expression of such altered nucleotideor peptide sequences produces variants which may be glycosylated atthose sites.

Additional analogs and derivatives of the sequence of the selectedcytokine which would be expected to retain or prolong its activity inwhole or in part, and which are expected to be useful in the presentmethod, may also be easily made by one of skill in the art. One suchmodification may be the attachment of polyethylene glycol (PEG) ontoexisting lysine residues in the cytokine sequence or the insertion ofone or more lysine residues or other amino acid residues that can reactwith PEG or PEG derivatives into the sequence by conventional techniquesto enable the attachment of PEG moieties.

Additional analogs of these selected cytokines may also be characterizedby allelic variations in the DNA sequences encoding them, or inducedvariations in the DNA sequences encoding them. It is anticipated thatall analogs disclosed in the above-referenced publications, includingthose characterized by DNA sequences capable of hybridizing to thedisclosed cytokine sequences under stringent hybridization conditions ornon-stringent conditions (Sambrook et al., Molecular Cloning. ALaboratory Manual, 2d edit., Cold Spring Harbor Laboratory, New York(1989)) will be similarly useful in this invention.

Also considered as derivatives useful in these methods are fusionmolecules, prepared by fusing the sequence or a biologically activefragment of the sequence of one cytokine to another cytokine orproteinaceous therapeutic agent, e.g., IL-11 fused to IL-6 (see, e.g.,methods for fusion described in PCT/U.S.91/06186 (WO92/04455), publishedMar. 19, 1992). Alternatively, combinations of the cytokines may beadministered together according to the method.

Thus, where in the description of the methods of this invention IL-11 ismentioned by name, it is understood by those of skill in the art thatIL-11 encompasses the protein produced by the sequences presentlydisclosed in the art, as well as proteins characterized by themodifications described above yet which retain substantially similaractivity. Standard laboratory tests are utilized to monitor progress ofthe treatment. Levels of TNF-α in serum or the biologic effects of TNF-αcould be followed in a variety of these diseases. Decreasedsymptomatology could also be used to monitor the effectiveness oftreatment as is well known to physicians skilled in the art of treatingsuch disorders. Treatment is preferably prophylactic, but may also be atthe onset of symptoms associated with the aforementioned disorders.

In one aspect of the invention, IL-11 is used in a therapeuticcomposition to alleviate or prevent the onset of symptoms associatedwith an inflammatory disorder. While it is possible to administer IL-11alone, it is believed preferable to present it as part of apharmaceutical formulation. In accordance with this aspect of theinvention, the pharmaceutical compositions comprise IL-11 in atherapeutically effective dose together with one or morepharmaceutically acceptable carriers and optionally other therapeuticingredients. A wide variety of pharmaceutically acceptable carriers areknown to those of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 17th ed.(1985), which is incorporated by reference herein. Preferred carriersinclude inert, non-toxic solids (e.g., dextrose, dextrin, cellulose,pectin, starch, lactose, sucrose, and calcium phosphate, ), semi-solids(e.g., glycerol stearate, polyethylene glycol, stearic acid, agar,gelatin, and propylene glycol) and liquids (e.g., buffered saline,water, an organic solvent, and pharmaceutically acceptable oils orfats).

As will be appreciated by those of skill in the art, the preferred formof the pharmaceutical composition of IL-11 will depend on the intendedmode of administration, which in turn will depend on the location andnature of the inflammatory disorder to be treated. For example, deliveryto the mouth (e.g., for treatment of oral mucositis, aphthous ulcers,gingivitis, periodontitis), head and/or neck (e.g., for treatment ofpharyngitis, esophagitis) can be in the form of aqueous-based oralsolutions, suspensions, emulsions, syrups, elixirs, gels, patches,lozenges, tablets, or capsules. Delivery to the gastrointestinal tract(e.g., for treatment of gastrointestinal mucositis, peptic ulcers andinflammatory bowel diseases, such as Crohn's disease, ulcerativecolitis, indeterminate colitis, and infectious colitis) can be in theform of oral solutions, gels, suspensions, tablets, capsules, and thelike. IL-11, either alone or in combination with other components in apharmaceutical composition, can be added to infant formula for deliveryto the gastrointestinal tract of an infant suffering from or susceptibleto necrotizing enterocolitis. It is also possible to formulate the IL-11preparation for rectal administration (e.g., for treatment ofproctitis), e.g., in the form of enema, suppositories, rectal-foam, andthe like. Delivery to the eye (e.g., for treatment of ocular diseasessuch as conjunctivitis, retinitis, and uveitis) can be in the form ofsolutions, gels, or suspensions. Delivery to the nose (e.g., fortreatment of nasal mucositis) can be in the form of solutions, gels, orsuspensions. The intranasal formulations may be formulated, for example,into an aqueous or partially aqueous solution, which can then beutilized in the form of a nasal drop or an aerosol. Delivery to the skin(e.g., for treatment of psoriasis) can be in the form of aqueous-basedsolutions, gels, suspensions, lotions, creams, ointments, patches, andthe like.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal administration include water (partially containing additives asabove), alcohols (including monohydric alcohols and polyhydric alcohols,e.g., glycols) and their derivatives, oils (e.g., peanut oil, sesameoil, olive oil, and coconut oil), and combinations of the above.Compositions comprising such carriers and adjuvants may be formulatedusing well known conventional materials and methods. Such materials andmethods are described, for example, in Remington's PharmaceuticalSciences, supra. Infant formula is also a suitable liquid carrier,particularly when the pharmaceutical composition is used to treat orprevent necrotizing enterocolitis.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aids, binders or tablet-disintegrating agents; it can alsobe an encapsulating material. In powders, the carrier is a finelydivided solid which is in admixture with the finely divided activeingredient. In tablets, the active ingredient is mixed with a carrierhaving the necessary compression properties in suitable proportions andcompacted in the shape and size desired. The powders and tabletpreferably contain up to 99% of the active ingredient, and may beformulated for immediate and/or sustained release of the activeingredient. Suitable solid carriers include, for example, calcium orsodium phosphate, magnesium stearate, talc, sugars, glycine, lactose,dextrin, starch, gelatin, cellulose, cellulose derivatives (e.g., methylcellulose, hydroxypropylmethyl cellulose, and sodium carboxymethylcellulose), polyvinylpyrrolidone, low melting point waxes, andcombinations of the above.

Oral tablets may be prepared using a variety of well known methods andin a variety of conventional forms. Exemplary forms include dry powdercompaction tablets, micro-particulate systems (e.g., wherein the activeingredient is spray-dried onto a scaffold particle), and hard orsoft-gel capsules. The tablets may be optionally covered with an entericcoating, which remains intact in the stomach, but will dissolve andrelease the contents of the tablet once it reaches the small intestine.Most currently used enteric coatings are those which remainundissociated in the low pH environment of the stomach, but readilysolubilize when the pH rises to about 4 or 5. A number of commerciallyavailable enteric coatings may be used depending on the target part ofthe intestinal tract, i.e., the site of the inflammatory bowel disorderin the patient. Such coatings include, for example, methacrylicacid-methacrylic acid ester-based copolymer, which is sold under thetrade name “Eudragit”; anionic water-soluble, polymer cellulose ether,which is sold under the trade name “Aqualon”; cellulose acetatephthalate; polyvinyl acetate phthalate; hydroxypropyl methylcellulosephthalate; and the like. Compositions comprising such carriers andadjuvants may be formulated, and tablets prepared from suchcompositions, using well known conventional materials and methods. Suchmaterials and methods are described, for example, in Remington'sPharmaceutical Sciences, supra.

In one embodiment of the invention, the pharmaceutical compositioncomprises one or more sustained or controlled release excipients suchthat a slow or sustained, preferably constant, release of the activeingredient is achieved. A wide variety of suitable excipients are knownin the art and are not a part of this invention. Suchsustained/controlled release excipients and systems are described, forexample, in U.S. Pat. No. 5,612,053 (Baichwal et al.), U.S. Pat. No.5,554,387 (Baichwal), U.S. Pat. No. 5,512,297 (Baichwal), U.S. Pat. No.5,478,574 (Baichwal et al.), and U.S. Pat. No. 5,472,711 (Baichwal etal.), each of which is incorporated by reference herein. If desired, thepharmaceutical composition can be formulated to provide a pulse dose ofthe active ingredient. A variety of pulse-dose systems, which providelow or high-pulsed doses, are known in the art and are not a part ofthis invention. Such pulse-dose formulations are described, for example,in Y. H. Bae, “Stimuli-Sensitive Drug Delivery,” Controlled DrugDelivery (ed. K. Park) ACS Press, Washington, D.C. (1997); Drugs (1982)23:207-226; Fertil. Steril. (1983) 39:695-699, 1983; Brit. J. Cancer(1982) 45:86-94; Int. J. Radiat. Oncol. Biol. Phys. (1982) 8:915-919; J.Clin. Endocrinol. Metab. (1981) 53:184-91; and Diabetes (1977)26:571-581.

In another embodiment of the invention, the pharmaceutical compositionis formulated to provide direct and/or targeted delivery of the activeingredient to a specific anatomic site or sites within thegastrointestinal tract; e.g., the duodenum, jejunum, ileum, cecum and/orcolon, each of which is believed to contain receptors for IL-11. Methodsfor providing targeted delivery of macromolecules, including proteinsand polypeptides, to specific tissues or organs within a mammalian hostare well known in the art and not a part of this invention. Suchtargeted delivery systems are described, for example, in R. J. Mrsny,“Site-Specific Drug Delivery in the Gastrointestinal Tract,” ControlledDrug Delivery, supra; M. Mezei and D. Meisner, “Liposomes andNanoparticles as Ocular Drug Delivery Systems,” Biopharmaceutics ofOcular Drug Delivery, Ch. 6 (ed. P. Edman) CRC Press, Boca Raton, Fla.(1992); T. L. Bowersock and H. Hogenesch, “Oral Immunization UsingMicroparticles,” Controlled Drug Delivery, supra; M. Mezei, “Liposomesin Topical Application of Drugs,” Liposomes as Drug Carriers: Trends andProgress (ed. G. Gregoriadis), J. Wiley & Sons Publ. USA (1988), pp.663-677; and J. J. Berti and J. J. Lipsky, “Transcutaneous DrugDelivery: A Practical Review,” Mayo CLW Proc. (1995) 70:581-586.

IL-11, either alone or in combination with other therapeutic agents, mayalso be administered topically in the form of a dermal patch ortransdermal delivery system. Such patches and systems are especiallysuited for treatment of inflammatory skin disorders such as psoriasis,and for inflammatory disorders involving the mucosa of the head, neckand/or mouth, e.g., oral mucositis, pharyngitis, esophagitis,gingivitis, perodontitis, and aphthous ulcers. In this embodiment of theinvention, the pharmaceutical composition may be administered throughthe use of a dermal patch containing the active ingredient(s) and acarrier that is inert to the active ingredient(s), non-toxic to the skinor mucosal epithelium, and allows delivery of the agent to the dermisand/or epithelium. Dermal patches and delivery systems, utilizing activeor passive transdermal delivery carriers, comprising IL-11 may beprepared suing well known methods and materials, including, for example,microporous membranes, silicon polymers and diffusion matrixes. Suchmaterials and methods are described, for example, in Remington 'sPharmaceutical Sciences, supra.

In yet another embodiment of the invention, at least one proteinaseinhibitor is combined with IL-11 in a therapeutic composition to treatinflammatory diseases. In accordance with this aspect of the invention,the pharmaceutical composition comprises IL-11 and one or moreproteinase inhibitors, which stabilize the IL-11 molecule againstproteolytic degradation. It may be preferable to include a proteinaseinhibitor in the pharmaceutical composition to protect IL-11 againstproteolytic enzymes in the gastrointestinal tract, particularly inrectal formulations. A wide variety of suitable proteinase inhibitorsare known in the art and are not a part of this invention. Suitableproteinase inhibitors include, for example, aprotinin, akallikrein-trypsin inhibitor, and protein serine proteinase inhibitorssuch as α-macroglobulin, soybean trypsin inhibitor, and ovomucoid.

A suitable treatment regimen for patients undergoing treatment,including for example prophylactic treatment, may be determined by theattending physician based upon such factors as the patient's age, sex,weight, and general health. Generally, a suitable dose of IL-11 rangesbroadly, preferably between about 1 and about 250 microgram (μg) perkilogram (kg) of body weight of recipient per treatment. Anothersuitable dose may be in the range of about 1 to about 100 μg per kg ofbody weight, and more preferably in the range of about 10 to about 50 μgper kg of body weight. If desired, these doses can be adjusted to units.A unit is conventionally described as the concentration of polypeptidewhich leads to half-maximal stimulation in a suitable assay, e.g., forIL-11, the T1165 assay described in PCT/US90/06803. Doses may beadministered daily for between one day and six months, or for as long asis deemed necessary and safe, as is readily ascertained by standardtests by the attending physician, depending upon the nature of thedisorder being treated. Where appropriate, the dosages may be adjustedupward or downward, for example, a dosing regimen requiringadministration of IL-11 at a dose of 25 μg/kg, daily for one week, orfewer days, or multiple weeks if indicated. The progress of treatment isappropriately monitored by measurement of markers associated with thedisorder being treated to determine if such a dose results in a decreaseof for example, TNF-α levels (or corresponding marker) and if not,increasing the dose two-fold for an additional time period of treatmentand measurement of marker levels until an effective dosing regimen isreached.

The following examples illustrate the methods of the present inventionand in particular the use of topical IL-11 formulations in treatingCrohn's disease, chemotherapy-induced ulcerative mucositis, colitis(colonic ulcers), psoriasis, and inflammatory bowel disease. However, asthe skilled artisan will recognize from the present disclosure, numerousmodifications and variations are possible and comprised within thepresent invention. The examples are not exhaustive, and do not limit thescope of the invention in any way.

EXAMPLE 1 Treatment of Inflammatory Bowel Disease

In two well-established models it has been shown that subcutaneousrhIL-11 is able to significantly reduce the clinical signs andhistologic lesions of gastrointestinal inflammation: acetic acid-inducedcolitis, a model of acute injury; and the HLA-B27 transgenic rat, amodel of chronic inflammation. While conducting further studies of themechanism of rhIL-11 action, oral topical activity was seen in hamsterswith 5-FU induced oral mucositis and mucosal activity was documented inin vitro/ex vivo studies of intestinal transport. Subsequently, thesemodels have been used to confirm the effectiveness of topically andorally administered rhIL-11.

Applicants first examined local topical delivery of rhIL-11 to the colonby enema. To determine the stability of rhIL-11 in the lumen of the gut,rhIL-11 and intestinal chyme from HLA-B27 rats were combined andincubated at 37° C. for up to several hours in the presence or absenceof a proteinase inhibitors. Fluid samples were analyzed periodically bySDS-PAGE. The addition of a proteinase inhibitor, avian ovoinhibitor,stabilized rhIL-11 against the proteolytic degradation observed in therat chyme. Next, twenty-three HLA-B27 rats (22-23 weeks old) wererandomized to one of six treatment groups: rhIL-11 Vehicle; 50 μg/mlovoinhibitor; rhIL-11 200 μg/ml; or rhIL-11 at 50, 200 or 800 μ/mlcombined with 50 μg/ml of ovoinhibitor. Animals received a colonicirrigation (1 ml) of the respective formulations, Monday, Wednesday andFriday, for three weeks. Stool character was assessed daily. At the endof the experiment, terminal blood samples were obtained, and then theanimals were euthanized by an overdose of anesthetic. Platelet countsand colonic mucosal lesions were quantitated and analyzed as describedpreviously. Platelet counts were not different in any of the groups. Inthe vehicle treated animals, normal, soft or diarrhea stools werepresent at 16.5, 33, or 50% of the total animal observation days,respectively. In the 50 μg/ml+50 μg/ml ovoinhibitor animals, normal,soft, or diarrhea stools were present at 65.9, 25, or 9.1% of the totalanimal observation days, respectively. Histologic lesion scores were7.25±1.4 and 7.8±1.4 in the vehicle and ovoinhibitor groups,respectively. ANOVA testing showed that all of the rhIL-11 lesion scoreswere lower than either vehicle or ovoinhibitor (P<0.05), and the lowestlesion score was in the 50 μg rhIL-11+50 μg ovoinhibitor group, 2.1±0.4.Topically administered rhIL-11 was beneficial in the model of chronicinflammatory bowel disease when combined with a proteinase inhibitor.Since this study was based around a dose of 200 μg/ml, no dosing groupof 50 μg/ml without the proteinase inhibitor was included.

Next, the effects of lower doses of recombinant human interleukin eleven(rhIL-11) with or without Aprotinin (an FDA approved and marketedProteinase inhibitor) delivered by enema were assessed in the aceticacid model of acute colitis. Colitis was induced in the descendingcolons of 80 anesthetized Sprague-Dawley rats by intraluminalinstillation of 10% acetic acid for 10 seconds on Day 0 of the study.The rats were randomly assigned to the 8 groups according to theirdifferent treatments as described below: TABLE 1 Group No. AnimalsDosage Schedule 1 Vehicle 10  1 ml. Buffer 3 days/wk/2 wks. 2 Aprotinin10 50 μg/ml 3 days/wk/2 wks. 3 & 4 rhIL-11 ± 20 10 μg/μg/ml 3 days/wk/2wks Aprotinin 5 & 6 rhIL-11 ± 20 25 μg/g/ml 3 days/wk/2 wks Aprotinin 7& 8 rhIL-11 ± 20 50 μg/ml 3 days/wk/2 wks Aprotinin

Peripheral hematologic parameters were assessed. On day 15, the animalswere euthanized, and colons were removed for determination of lesionscores by gross examination and histologic evaluation. Platelet countsin all groups were in normal range. All animals treated with acetic aciddeveloped diffuse colonic lesions, characterized by ulceration,hemorrhage, edema, depletion of goblet cells, and infiltration ofleukocytes. The gross and histologic lesions of all rhIL-11 treatedanimals were significantly reduced compared with vehicle controls on day15. Administration of rhIL-11 10 μg with 50 μg Aprotinin 3 days/week/for2 weeks or 50 μg/ml rhIL-11 3 days/wk/2 wks appeared to be mosteffective in this model of colonic mucosal injury.

EXAMPLE 2 Treatment of Oral Mucositis

95 male Golden Syrian hamsters were equally divided into five groups.Group 1 [control] received phosphate buffered saline and 0.5% hamsterserum (vehicle) topically on days 3-14. Groups 2 and 4 received 50 μgIL-11 subcutaneously, twice daily, on days 0-14 and 3-14, respectively.Groups 3 and 5 received 100 μg IL-11 topically, four times daily, ondays 3-14 and 0-14, respectively. Ulcerative mucositis was induced byadministration of 60 mg/kg body weight of 5-fluorouracil on days 0 and2. The left buccal pouch was superficially irritated on day 4.Ulcerative mucositis was evaluated blindly starting on day 6 by scoringstandardized photographs. The scoring was done on a scale of 0-10, with10 being the most severe. Animals were weighed daily. Blood was takenfrom 3 animals per group on days 6, 10 and 14.

For the entire experiment, average mean ulcerative mucositis scores forall groups were significantly [p<0.05] lower than control. [G1=5.0;G2=3.8; G3=4.1; G4=3.3; G5=4.0]. Day 14 survival rates for G1 through G5were 23%; 69%, 38%, 100% and 46%, respectively. Thus, topicaladministration of IL-11 was shown to favorably modify the course ofchemotherapy-induced ulcerative mucositis relative to control.

The present investigation demonstrates the beneficial effects of atopical formulation of recombinant human IL-11 (rhIL-11) on theinduction, course and resolution of chemotherapy-induced mucositis.

Materials and Methods

Male LVG Golden Syrian hamsters (Charles River Laboratories, Wilmington,Mass.), aged 5-6 weeks, were caged in small groups and fed standardhamster chow and water ad libitum. All procedures were conducted inaccordance with guidelines set by the Harvard Medical Area StandingCommittee on Animals.

Mucositis induction and evaluation

All procedures were performed using anesthesia induced by diethyl ether.To induce mucositis, 5-fluorouracil was administered (60 mg/kg) byintraperitoneal injection on days 0 and 4. To mimic the functionaltrauma, which occurs in humans, the left buccal pouch mucosa wassuperficially irritated on day 4. Animals were weighed and observeddaily through day 14. Mucositis was evaluated on days 6 to 14. Toevaluate mucositis, animals were anesthetized and the cheek pouch waseverted, immobilized, and photographed using a standard, validatedtechnique. At the conclusion of the study, all film was developedsimultaneously. Photographs were numbered, randomized and graded blindlyby three independent observers using a 10-point scale in which mildmucositis equaled a score of 1 to 3, moderate 4 to 6, and severe greaterthan 6. Mild mucositis was defined as mucosal erythema withvasodilation. Mold mucositis was defined as ulceration withpseudomembrane formation, erythema and vasodilation, and severemucositis consisted of diffuse ulceration with extensive areas ofnecrosis, pseudomembranes, erythema and vasodilation.

Test groups and protocol

Ninety-five animals were prospectively randomized into five equalgroups. Each animal was individually numbered using an ear punchtechnique. The following groups were studied: Group 1 Vehicle control,topical, four times daily, days 3 to 14 (day 0 = day of firstchemotherapy injection). Group 2 100 μg IL-11 per day in a divided dosegiven twice daily, subcutaneously, days 0-14. Group 3 400 μg IL-11 perday in a divided dose given four times daily, topically, days 3-14.Group 4 100 μg IL-11 per day in a divided dose given twice daily,subcutaneously, days 3-14 Group 5 400 μg Il-11 per day in a divided dosegiven four times daily, topically, days 0-14.

Animals in the Group 1 were treated with topical application of PBScontaining 0.5% hamster serum. Animals in the test groups receivedrhIL-11 made up in PBS containing 0.5% hamster serum. Animals receivingtopical therapy received treatment at 9 a.m., 11:30 a.m., 2 p.m. and4:30 p.m. Animals receiving injections of IL-11 were treated at 9 a.m.and 4 p.m. Whole blood was obtained on days 6 and 14 to evaluated thenumber of platelets.

Results

Cumulative mean mucositis scores for group 2 (3.0) and group 4 (2.7)were markedly less than that noted for the control (4.7). Topicalapplication of rhIL-11 was of benefit (group 3=3.3; group 5=3.4), thoughslightly less efficacious than rhIL-11 delivered by the subcutaneousroute. Interestingly, the efficacy of rhIL-11 given by either route wasessentially comparable after day 10. Marked rhIL-11 benefit was notedfrom day 6 through day 14 among animals treated via the subcutaneousroute. On days 6, 7, and 8, animals in group 2 (IL-11 from day 0) hadslightly less mucositis than did animals in group 4 (IL-11 beginning onday 3). On day 9 this trend was reversed. No difference was seen for theremaining days of the study.

Schedule of rhIL-11 administration had no observed effect on its topicalefficacy, with no significant differences observed between scores ofanimals in groups 3 and 5. Less mucositis was observed in animalstreated with topically applied rhIL-11 throughout the course of theexperiment. Reduction in mucositis scores was essentially equivalentbetween both topical groups. Interestingly, the effect of topicallyapplied rhIL-11 was the same as the subcutaneously administered peptidefrom day 11 to the conclusion of the experiment.

Evaluation of the effect of rhIL-11 on moderate to severe mucositisdemonstrated a similar trend. From day 6 to day 9, the percentage ofcontrol animals (group 1) with moderate to severe mucositis was markedlygreater than that noted in animals treated with rhIL-11. In general,animals treated subcutaneously responded more favorably. For example, onday 8, 67% of control animals had mucositis scores equal to or greaterthan 5 compared to 13% of animals in group 2 and 31% of animals in group4. The frequency of animals in the topically treated groups was 42%(group 3) and 39% (group 5). This trend appears to have shifted on days10 to 11 where it appears that topically treated animals did better thanthose injected with rhIL-11. While this is true of surviving animals,evaluation of survival data is of importance in interpreting thisapparent trend.

The above results demonstrate that topical administration of rhIL-11 isbeneficial in vivo for the treatment of oral mucositis.

EXAMPLE 3 Treatment of Colitis (Colonic Ulcers)

The effects of three different dosages of recombinant humaninterleukin-11 (rhIL-11), given subcutaneously (SC) either prior to orsubsequent to intracolonic administration of trinitrobenzene sulfonicacid (TNB), were studied in Sprague-Dawley rats. The TNB or control weregiven in a 40% ethanol solution to 312 anesthetized adult male ratsallotted to one of 26 groups (n=12). Control groups were: subcutaneous(SC); saline alone; intrarectal (IR); 40% ethanol alone; TNB alone; 40%ethanol alone, and SC, rhIL-11 at the highest dosage alone and groupscombining TNB with rhIL-11 therapy, testing three dosages (100, 300, and1,000 μg/kg), given either before or after induction of colitis withTNB. Body weight changes were monitored. Rats were euthanized at 3 days,7 days, or 14 days after TNB administration. At necropsy, samples werecollected to evaluate fecal occult blood, mucosal myeloperoxidaseactivity and mucosal gross indexes of ulceration. Histopathologic andultrastructural analyses of the colonic mucosa were performed. The TNBalone elicited a prolonged, severe colitis in treated animals, and theethanol control group showed a short-lasting, less severe colonicinflammatory response. Colonic ulcer indexes of rhIL-11 treated ratsshowed a consistent, dose-related reduction in the severity of theTNB-induced colitis, whether the interleukin was given before or afterthe TNB. This reduction was significant (P<0.05) after administration ofthe intermediate (300 μg/kg) and highest (1,000 μg/kg) dose levels ofrhIL-11, in the groups given rhIL-11 for 7 days after TNB.Myeloperoxidase activity was increased during the TNB-induced colitisand was reduced by rhIL-11 administration (P<0.01). Fecal occult bloodloss increased with colitis and paralleled its severity. rhIL-11enhanced mucus production and decreased the severity of TNB-inducedcolitis.

EXAMPLE 4 Treatment of Mucositis

One of the dose-limiting toxicities of radiation therapy for head andneck cancer is the occurrence of oral mucositis. The effects of topicaladministration of IL-11 on this effect are examined in conjunction withat least one of several regimens employed for the treatment of advancedhead and neck cancer. The specifics of the regimens vary, and mayinclude external beam standard fractionated irradiation,hyperfractionated irradiation, or accelerated fractionated irradiation.Various chemotherapy agents may also be employed either sequentially orconcurrently with radiotherapy. Chemotherapy agents frequently employedin this setting include 5-fluorouracil (5-FU), cisplatin, carboplatin,hydroxyurea, paclitaxel, and topotecan, either alone or in variouscombinations.

One regimen is outlined for the purpose of illustration. The regimeninvolves hyperfractionated external beam irradiation and concurrentchemotherapy with infusional 5-FU and cisplatin. This regimen has beenemployed for several years for patients with locally advanced squamouscell carcinoma of the head and neck. Patients receive 125 centi-Gray(cG) twice per week of external beam irradiation 5 days per week. Thetotal planned dose is 7000 cG. During weeks 1 and 6 of radiotherapy,patients are treated with 5-FU and cisplatin. 5-FU is administered as a5-day continuous infusion of 600 mg/m/day while cisplatin isadministered as a bolus injection of 12 mg/m/day for 5 days. There is a7-day scheduled treatment break after 4000 cG to allow mucositis tosubside. The entire planned time for completion of the course ofirradiation and concurrent chemotherapy is 7 weeks.

Patients are randomly assigned in a ratio of 2:1 to receive eithertopical IL-11 or placebo. Patients receiving IL-1 will receive either 50ug/L or 150 μg/mL in 15 to 30 mL of Brioschi (sodium bicarbonate). A 5mg vial of IL-11 or excipient alone [placebo] first will be resuspendedwith 1 mL water for injection (WFI). When 30 mL of Brioschi is used, 300μL (for 50 ug/mL dose) or 950 μL (for the 150 ug/mL dose) containingeither IL-11 or excipient alone will be removed from the vial and addedto 30 mL Brioschi. This final preparation, containing either IL-11 orplacebo excipient alone, is swished and swallowed twice daily for 6 to 8weeks beginning the day before radiotherapy. All patients are assessedto determine the effects of the topical preparation of IL-11 on patientsreceiving chemotherapy and/or radiotherapy for head and neck cancer.Among the endpoints summarized are:

-   -   Incidence of oral mucositis of Grade 3 or higher, as measured by        the modified National Cancer Institute Common Toxicity Criteria;    -   Duration of oral mucositis of Grade 3 or higher. Duration is        measured as (1) the time from onset of Grade 3 or higher until        resolution to less than Grade 3 and    -   (2) the number of days of oral mucositis of Grade 3 or higher;    -   Total duration of oral mucositis of any grade;    -   Maximum severity of oral mucositis experienced during the study;    -   Incidence of hospitalization due to oral mucositis; and    -   Incidence of IV fluid resuscitation due to dehydration secondary        to poor oral intake [secondary to mucositis].        Patients receiving IL-11 exhibit significant improvement in one        or more of the above criteria.

EXAMPLE 5 Treatment of Psoriasis

The effects of IL-11 in modulating keratinocyte (the target cell type ina number of cutaneous inflammatory skin diseases, including psoriasis)growth and gene expression were assessed in vitro. When rhIL-11(recombinant human IL-11) was added to a basal culture medium at aconcentration of 100 ng/mL, it stimulated keratinocyte proliferation.RT-PCR analysis showed that keratinocytes grown in basal as well asenriched medium expressed IL-11 receptor α-chain mRNA (IL-11Rα). rhIL-11was able to stimulate phosphorylation of STAT-3 in keratinocytes whengrown in basal medium. To assess whether rhIL-11 could affect the levelsof surface intercellular adhesion molecule-1 (ICAM-1) induced by IFN-γand TNF-α, ketaninocytes were exposed to IFN-γ and TNF-α for one hourbefore adding rhIL-11. Addition of rhIL-11 resulted in a significantdecrease in the amount of surface ICAM-1. These results show that IL-11has direct effects on keratinocytes, thereby downregulating cutaneousimmune responses.

While the present invention has been described in terms of specificmethods and compositions, it is understood that variations andmodifications will occur to those skilled in the art upon considerationof the present invention.

Numerous modifications and variations in the invention as described inthe above illustrative examples are expected to occur to those skilledin the art and, consequently, only such limitations as appear in theappended claims should be placed thereon. Accordingly, it is intended inthe appended claims to cover all such equivalent variations which comewithin the scope of the invention as claimed.

The disclosure of all of the publications cited herein are herebyincorporated by reference.

1. A method of treating an inflammatory disorder, comprisingadministering a topical formulation of a pharmaceutical compositioncomprising a pharmaceutically effective amount of IL-11.
 2. The methodof claim 1 wherein the disorder is mucositis.
 3. The method of claim 2wherein the mucositis is oral mucositis.
 4. The method of claim 2wherein the mucositis is gastrointestinal mucositis.
 5. The method ofclaim 1 wherein the disorder is an inflammatory skin disorder.
 6. Themethod of claim 5 wherein the inflammatory skin disorder is psoriasis.7. The method of claim 1 wherein the disorder is necrotizingenterocolitis.
 8. The method of claim 1 wherein the disorder is anocular disease.
 9. The method of claim 8 wherein the ocular disease isselected from the group consisting of conjunctivitis, retinitis anduveitis.
 10. The method of claim 1 wherein the disorder is selected fromthe group consisting of aphthous ulcers, pharyngitis, esophagitis,peptic ulcers, gingivitis, and periodontitis.
 11. The method of claim 1wherein the pharmaceutically effect amount of IL-11 is between about 1and about 250 μg/kg body weight.
 12. The method of claim 1, wherein thepharmaceutical composition comprises a solution containing IL-11 and asuitable liquid carrier.
 13. The method of claim 12, wherein thesuitable liquid carrier is selected from the group consisting of water,organic solvents, oils and fats.
 14. The method of claim 12, wherein thesuitable liquid carrier is sodium bicarbonate.
 15. The method of claim12, wherein the suitable liquid carrier is an infant formula.
 16. Themethod of claim 1, wherein the pharmaceutical composition comprises animmediate release carrier for immediate release of IL-11 into the oralcavity.
 17. The method of claim 16, wherein the immediate releasecarrier is selected from the group consisting of sugars, glycine,lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. 18.The method of claim 16, wherein the topical formulation is selected fromthe group consisting of an oral gel, tablet or suspension.
 19. Themethod of claim 1, wherein the pharmaceutical composition comprises animmediate release carrier for delivery of IL-11 to the gastrointestinaltract.
 20. The method of claim 19, wherein the immediate release carrieris selected from the group consisting of sugars, glycine, lactose,dextrin, starch, gelatin, cellulose, methyl cellulose,hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. 21.The method of claim 19, wherein the topical formulation is a pill,tablet or capsule.
 22. The method of claim 1, wherein the pharmaceuticalcomposition comprises a sustained-release carrier for delivery of IL-11to the oral cavity.
 23. The method of claim 21, wherein the topicalformulation is a patch, lozenge or an uncoated tablet.
 24. The method ofclaim 1, wherein the pharmaceutical composition comprises asustained-release carrier for delivery of IL-11 to the gastrointestinaltract.
 25. The method of claim 24, wherein the topical formulation is apill, tablet or capsule.
 26. The method of claim 1, wherein thepharmaceutical composition comprises an immediate release carrier fordelivery of IL-11 for cervical administration.
 27. The method of claim25, wherein the topical formulation is selected from the groupconsisting of a topical cream, solution, ointment, and gel.
 28. Themethod of claim 1, wherein the pharmaceutical composition comprises asustained-release carrier for delivery of IL-11 for cervicaladministration.
 29. The method of claim 26, wherein the topicalformulation is a topical cream, solution, ointment or gel.
 30. Themethod of claim 1, wherein the pharmaceutical composition comprises anenema preparation of IL-11 and a suitable liquid carrier for delivery tothe colon.
 31. The method of claim 1, wherein the pharmaceuticalcomposition comprises a proteinase inhibitor.
 32. The method of claim31, wherein the proteinase inhibitor is selected from the groupconsisting of aprotinin, α-macroglobulin, soybean trypsin inhibitor, andovomucoid.
 33. The method of claim 31, wherein the proteinase inhibitoris aprotinin.
 34. The method of claim 1, wherein the topical formulationcomprises an enteric coating.
 35. The method of claim 34, wherein theenteric coating is selected from the group consisting of a methacrylicacid-methacrylic acid ester-based copolymer, an anionic water-solublepolymer cellulose ether, cellulose acetate phthalate, polyvinyl acetatephthalate, and hydroxypropyl methylcellulose phthalate.
 36. Acomposition for treating an inflammatory disorder, wherein saidcomposition is a topical formulation comprising a pharmaceuticallyeffective amount of IL-11 and a suitable liquid carrier.
 37. Thecomposition of claim 36, wherein said suitable liquid carrier is sodiumbicarbonate.
 38. The composition of claim 36, wherein said suitableliquid carrier is an infant formula.
 39. A composition for treating aninflammatory disorder, wherein said composition is a topical formulationcomprising a pharmaceutically effective amount of IL-11 and a suitablesolid carrier.
 40. The composition of claim 39, wherein said suitablesolid carrier is an immediate release carrier.
 41. The composition ofclaim 40, wherein said immediate release carrier is selected from thegroup consisting of sugars, glycine, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, hydroxypropylmethyl cellulose, and sodiumcarboxymethyl cellulose.
 42. The composition of claim 39, wherein saidsuitable solid carrier is a sustained-release carrier.
 43. Thecomposition of claim 39, wherein said suitable solid carrier comprises aproteinase inhibitor.
 44. The composition of claim 39, wherein theproteinase inhibitor is selected from the group consisting of aprotinin,a-macroglobulin, soybean trypsin inhibitor, and ovomucoid.
 45. Thecomposition of claim 44, wherein the topical formulation comprises anenteric coating.
 46. The composition of claim 45, wherein the entericcoating is selected from the group consisting of a methacrylicacid-methacrylic acid ester-based copolymer, an anionic water-solublepolymer cellulose ether, cellulose acetate phthalate, polyvinyl acetatephthalate, and hydroxypropyl methylcellulose phthalate.